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United States Patent 3,211,738 D-3-METHOXY-N-METHYL-A -M0RPH1NAN AND SALTS THEREOF Yoshiro Sawa, Ashiya-shi, Shin Maeda, Amagasaki-shi, and Naoki Tsuji, Semboku-gun, Japan, assignors to Shionogi & Co., Ltd., Osaka, Japan No Drawing. Filed Aug. 6, 1962, Ser. No. 214,855 Claims priority, application Japan, Dec. 29, 1959, 34/41,?)50, 34/41,351, 34/ 41,352 3 Claims. ((11. 260--285) This invention relates to new morphinan derivatives, D-3-methoXy-N-methyl-A -morphinan and its salts. More particularly, this invention relates to D-3-methoxy-N- methyl-A -morphinan, its quaternary salts and its nontoxic acid addition salts, which are useful therapeutics having remarkable activities on the nervous system. In other aspects, this invention relates to related morphinan derivatives useful in the preparation of D-3-meth0Xy-N- methyl-A -morphinan as well as to a method for the purification of the latter. It also relates to the use of the said compound for therapeutic purposes.

This application is a continuation-in-part application of our co-pending application Serial No. 76,511, filed on December 19, 1960 (now U.S. Patent No. 3,085,091).

It is well known that compounds of the morphinan series have powerful analgesic or antitussive actions and that most compounds of the series have strong habit-forming attributes. On the contrary, the compound of the present invention shows very different pharmacological activities, e.g. potentiated narcosis, anti-eXtensor effect and suppression of aggressive behavior. Moreover, it has no analgesic and no antitussive activities, and no habit-forming attributes. No compound of the morphinan series having such properties has hitherto been known. Recently, it was reported by M. Gates et al. (J. Am. Chem. Soc., 80, 1186-1194) that 3-hydroXy-N- methyl-A -isomorphinan showed a strong analgesic activity, although it is a most similar compound to the known morphinan derivatives. Therefore, the compound of the present invention is a novel and very unique morphinan derivative having an enormous and broad usefulness as a therapeutic.

The compound of the present invention, D-3-methoxy- N-methyl-A -morphinan, can be prepared through various routes. Some of these may be represented by the schemes shown in column 3.

The starting material of this invention is sinomenine, one of alkaloids obtained from a plant Sin'omenium acutum. In this specification the morphinan nucleus of sinomenine is presented as D-morphinan and all the compounds are named on this basis.

Firstly, D-3,7-dimethQXy-4 hydrOXy-6 oxo-N-methyl- A -morphinan [I], sinomenine, is treated with halogenobenzene in a basic solvent in the presence of copper powder as catalyst to produce D-3,7-dimethoxy-4-phenoxy-6-oxo-N-rnetthyl-N-morphinan [II]. The compound [II] may be treated with amalgamated zinc in concentrated hydrochloric acid to give D-3-methoXy-4-phenoxy-N-methyl-A -morphinan [VII]. Alternatively, the compound [II] may be converted to D-3,7-dimethoxy- 3,211,738 Patented Oct. 12, 1965 "ice 4-phenoxy-6-oxo Nemethylmorphinan [III] by catalytic reduction and the latter may be ketalized to D-3,7-dimethoxy-4-phenoxy-6,6-ethylenedioxy-N methylmorphinan [IV]. On the other hand, the compound [II] may be hydrolyzed to D-3-methoxy-4-phenoxy-6-oxo-7-hydroxy-N-methyl-A' -morphinan [V] which is a tautomer of D-3-methoxy-4-phenoxy-6,7-dioXo-N methylmorphinan, and the compound [II] as well as the compound [V] may be ketalized to D-3-methoxy-4-phenoXy-6,6;7,7- bisethylenedioxy-N-methyl-morphinan [VI].

Compounds [III], [IV], [V], and [VI] may be also treated with amalgamated zinc in concentrated hydrochloric acid to yield compound [VII].

' Compound [VII] is treated with alkali-metal or alkaline-earth-metal in liquid ammonia to yield the objective compound [VIII], D-3-methoxy-Nmethyl-A -morphinan, of which chemical structure has been determined as follows:

(1) The catalytic reduction of compound [VIII] with one molecular equivalent of hydrogen results in D-3- methoxy-N-methylmorphinan, M.P. 109-111 C. which is identical with an authentic sample prepared by a method of O. Schnider et al. (Helv. Chim. Acta, 34, 2211; ibid, 37, 710).

(2) The oxidation of compound [VII] with osmium tetroxide produces corresponding dihydroxy-compounds [X], M.P. -126 C. and [XI], M.P. 177 C., and the former compound [X] is identical with a compound obtained by reduction of compound [V] with sodium boron hydride.

(3) The compound [VII] can be obtained by demesyloxylation of compound [XII] (the methiodide: M.P. 228 C. (decomp.)) which is prepared by mesylation of the compound [IX], M.P. 126-136 C., one of the reduction products of compound [V] with sodium boron hydride. .All the dihydroxy compounds, eg, [X] and [XI] can be also converted to compound [VII] by the same method.

Although thus produced compound [VIII] can be used as such, it is usually contaminated by a small quantity of by-products having closely similar structures. To obtain an absolutely purified compound [VIII], it is advantageous to carry out a purification at the step of compound [VII]. For this purpose, the crude compound [VII] may be converted by bromination to the corresponding 6,7-dibromide [XIII] which can be easily purified by recrystallizations as a hydrohalide, and then the 6,7-dibromide [XIII] may be treated with metallic zinc in acetic acid to regenerate the compound [VII], eliminating two bromine atoms. Alternatively, the crude compound [VII] may be converted to the corresponding N-oxide of the 6,7-epoxide by oxidation with per-acid and subsequently hydrogenated by catalytic reduction to give the 6,7-epoxide [XIV], which can be easily purified by recrystallization as a benzoate. Then, the epoxide [XIV] may be treated with hydrogen bromide to yield the corresponding bromohydrine [XV] and the latter may be treated with metallic zinc in acetic acid to regenerate the compound [VII].

n I H Corresponding dimesyloxy compounds These purification processes may be illustrated by the following formulae:

CHgO- OaHsO- W i [XIV] CH3O NCHa l [VII] I [XV] (p (in When thus purified compound [VII] is treated with alkali-metal or alkaline-earth-metal in liquid ammonia as described beforehand, the compound [VIII] can be obtained in an absolutely pure state.

The compound [VIII] is usually used as hydrohalide such as hydrochloride, hydrobrornide or hydroiodide, but

OCH 3 it may be used as quaternary salt with a lower alkyl halide containing up to five carbon atoms (e.g. methyl bromide, ethyl chloride, butyl bromide, etc.) or as a non-toxic acid addition salt such as sulfate, phosphate or the like.

Thus produced D-3-methoXy-N-methyl-A -morphinan [VIII] is a novel compound having a distinguished therapeutic usefulness.

The pharmacological properties of the compound are advantageously tested as hydrobromide-hydrate.

Its acute toxicity in mice is presented in Table I.

TABLE I LD (mg./kg.) Intravenous injection 68.8 Subcutaneous injection 147.4 Oral administration 190.1

TABLE II Time required Compounds for appearance EDso (mg/kg.)

of maximum effect (seconds) This compound 1 20 8. 7 Methyl Hexabital Sodium 5 40. 7 Diphenyl Hydantoin 30. 1

1 D-3-methoxy-N-methyl-A-morphinan (as hydrobromido-hydrate). This compound shows a strong suppression of fighting behavior in hamsters. 2S mg./kg. (s.c.) of this compound are as intensive as 75 mg./kg. (s.c.) of chloropromazine in hamsters. Moreover, 1-2 mg./kg. (s.c.) remarkably suppress aggressive behaviors of monkeys.

These remarkable properties show that the compound [VIII] is an eifective central nervous depressant, particularly is a very unique sedative agent.

No habit-forming attribute of or physical dependence on this compound is observed in rats and monkeys.

The compound [VIII] of this invention is useful as an anticonvulsant for treatment of epilepsy or the like and as a tranquilizer for treatment of metal disorders, especially for suppression of aggressive behavior.

The tranquilizing effect of this compound [VII] is much distinguished in its property of causing no sleepiness, which is a generally unavoidable incident of a usual tranquilizer.

Practical and presently preferred embodiments of this invention are illustrated by the following examples. The abbreviation g. refers to grams, and cc. to milliliters.

Example 1 OCH 3 A mixture of D-3,7-dimethoxy-4-hydroxy 6 oxo N- methyl-A morphinan [I] (16.5 g.), bromobenzene (15.7 g.), potassium carbonate (10.3 g.), copper powder (0.5 g.) and pyridine (50 cc.) is refluxed for 15 hours. The hot reaction mixture is filtered and washed with hot pyridine. The solvent is removed by distillation and the residue is dissolved in benzene. The benzene solution is filtered, washed with water, dried on potassium car- 3,2 1 1,738 7 8 bonate and chr-omatographed on alumina to yield 22 g. of ethanol is treated with an ethanolic solution of picric of crude product. Recrystallization from benzene g-ives acid. The yield of yellow crystalline picrate of D-3,7-di- 20.7 g. of the pure benzene adduct of D-3,7-dirnethoxy-4- methoxy-4phenoxy-6-oxo-N-methylmorphinan [III] is alphenoxy-6-oxo-N-methyl-A' -morphinan [II], M.P. 122- most quantitative, M.P. 208 C. (decomp.).

124 C. [111 111.9 (0.940% in ethanol). 5 Analysis.-Calcd. for C H O N-C H O N C, 58.84;

Analysis.Calcd. for C H O N-C H C, 76.99; H, H, 5.07; N, 8.80. Found: C, 58.02; H, 5.27; N, 8.32. 6.88; N, 2.90. Found: C, 76.92; H, 7.09; N, 2.76. A sample of the picrate is converted to the free base The pyridine adduct is separated on cooling the reacby partition between ether and iluted sodium hydroxide tion mixture and crystallizing from pyridine, M.P. 120- solution. The ether extracts are washed with diluted 123 C. [06113 116.4 (0.975% in ethanol). 10 sodium hydroxide solution and water, dried, filtered and Analysis.Calcd. for C H O N-C H N: C, 74.35; chromatographed on alumina, yielding a colorless oil H, 6.66; N, 5.78. Found: C, 74.51; H, 6.67; N, 5.78. which crystallizes on standing. Crystallization from ether The free base is crystallized from ether, M.P. 142-143 gives pure D-3,7-dimethoxy-4-phenoxy-6-oxo-N-methyl- C. [111 137.8 (0.994% in ethanol). morphinan [IH], M.P. 149154 C. [a] 5.9

Analysis.Calcd. for C H O N: C, 74.05; H, 6.75; (0.904% in ethanol). N, 3.45. Found: C, 73.94; H, 7.07; N, 3.27. Analysis.--Calcd. for C H O N: C, 73.68; H, 7.17;

The picrate is prepared in ether and crystallizes from N, 3.44. Found: C, 73.84; H, 7.25; N, 3.41. ethanol, M.P. 230-231 C. The methiodide is crystallized from ethanol, M.P. 255

Analysis.-Calcd. for C25H27O4N'C5H3O7N3Z C, 58.67; C. (decomp.). H, 4.77; N, 8.83. Found: C, 58.95; H, 4.93; N, 8.83. Analysis.Calcd. for C H O N-CH I: C, 56.83; H, The methiodide is prepared in and crystallizes from 5.87; N, 2.55; I, 23.10. Found: C, 56.57; H, 5.82; N, ethanol, M.P. 206 C. (decomp.). [041 121.5 2.44; I, 23.21.

(0.969% in ethanol). Example 3 CH3O CH3O CGHSO C6H5O bar-CH3 I 3 O .I 0 i CH 3 OCH [III [IV] Analysis.Calcd. for C H O N-CH I-C H OH: C, A benzene solution of D-3,7-dimethoxy-4-phenoxy-6- Found: oXo-N-methylmorphinan [III] (2.6 g.) and ethylene glycol 6.04; N, 2.42; I, 21.31. (5 cc.) is refluxed with toluene-p-sulfonic acid (2 g.) for Example 2 7 hours, and yields 2.9 g. of D-3,7-dimethoxy-4-phenoxy- A solution of the benzene adduct of D-3,7-dimethoxy- 6,6-ethylenedioxy-N-methyhnorphinan [IV] as a sirup 4-phenoxy-6-0Xo-N-methy1-A' -morphinan [H] (12 g.) in (essentially quantitative). [04], 56.2 (1.0% in ethanol (100 cc.) is hydrogenated over Adams catalyst ethanol).

(100 mg.) at room temperature (20 to C.). After The methiodide is prepared in and crystallizes from absorption of 700 cc. of hydrogen, the solution is filtered ethanol, M.P. 260 C. (decomp.). [111 46.2 and evaporated to dryness. The residue in a small] amount 7 (1.165% in ethanol).

3,211,738 9 10 Analysis.-Calcd. for C H O N-CH I: C, 56.66; H, (4 g.) and ethyleneglycol cc.) is refluxed with tol- 6.11; N, 2.36; I, 21.39. Found: C, 56.65; H, 6.13; N, uene-p-sulfonic acid (3.5 g.) for 7 hours with an azeo- 2.29; I, 21.75. tropic receiver to collect the volatile products. Upon cool- Example 4 ing, 10% sodium carbonate solution is added to give a A solution of the benzene adduct of D-3,7-dimethoxyslightly alkaline reaction and the two layers are separated. 4-phenoxy-6-oxo-N-methyl-A' -morphinan [II] (12 g.) in 5 The alkaline solution is extracted With chloroform and 10% hydrochloric acid (120 cc.) is heated for 2 hours the crude base is chromatographed on alumina, the on a water bath. Upon cooling, the solution is made chloroform eluate yielding 3 g. of D-3-methoxy-4-phebasic with aqueous sodium carbonate solution and noxy 6,6;7,7 bisethylene-dioxy N methylmorphinan the crystalline product is Washed with Water and crystal- [VI]. Crystallization from ethylacetate yields 2.6 g. of lized from methanol yielding 8.45 g. of pure D-3-methe pure product, M.P. 198200 C. [041 -37.6 thoxy 4 phenoxy 6-oxo-7-hydroxy-N-methyl-A7-mor- (1.037% in ethanol).

phinan [V], M.P. 212-214" C. 64.7 (1.043% Amalysis.-Calcd. for C H O N: C, 70.12; H, 6.94; in chloroform). N, 2.92. Found: C, 70.32; H, 6.94; N, 2.96.

y 'C24 25 4 s C, The rnethiodide is prepared in and crystallizes from H, 6.68; N, 3.44; OCH 11.42. Found: C, 72.37; H, 35 ethanol, p 1 Q 21 21 1 93% h. 6.61; N, 3.35; OCH 10.80. anon.

Example 5 Analysis.Calcd. for C H O N-CH I: C, 54.46; H,

OCH

A benzene solution of the benzene adduct of D-3,7-dillound 54'81; 6'18;

methoxy 4-phenoxy-6-oxo-N1methyl-A' -morphinan [II] Example 6 CH O 1 1 1 2 A benzene solution of D-3-methoxy-4-phenoxy-6-ox0- diluted sodium hydroxide solution and extracted with 7-hydroxy-N-methyl-A' -morphinan [V] (5 g-) and ether. The product is chromatographed on alumina and ylene glycol is reflllXed With toluene-p-slllfonic the ether eluate gives 2.43 g. of D-3-methoXy-4-phenoxyacid (4 g.) for 7 hours as described in the Example 5. h s morphinan 11 as a sirup zs The reaction mixture yields 4.76 g. of D-3-methoxy-4- 5 +5 (073% in ethanol) phenoxy'66;77'blsefllylenedloxy methylmorphman The free base does not crystallize, but its methanol ad- .198 200 and thls not depressed on duct is obtained as neadles when this sirup is treated admixture with the sample obtalned 1n the Example 5. with methanol 0 [0611322 +5150 HD2870 Example 7 in ethanol).

cn o

C6H5O rt-CH OCH [II] [VII] Amalgamated zinc (prepared from g. of mossy zinc Analysis.Calcd. for C H O N-CH OH: C, 76.30;

and 2 g. of mercuric chloride) is added in small pora, Found: tions to a hot solution of the benzene adduct of D-3,7- 30 Q 3 4-55- I dimethoxy 4 phenoxy 6 OXO N methYLA'Lmomhinan The methiodide 15 prepared in and crystallizes from [II] (3.6 g.) in concentrated hydrochloric acid (25 cc.) ethanol, 115 in 6thduring 2 hours. The mixture is heated on a water bath anon with stirring for 6 hours, during which time concentrated Anfllysls c alcd' for C24H27O2N'CH3I'C2H5OH' 59.01, H, 6.60, N, 2.55; I, 23.10. Found: C, 58.63; H,

hydrochloric acld (15 cc.) is added every 2 hours. The 6.67, N I 23 43 solution is cooled to room temperature, diluted with wa- The picrate is prepared in and crystallizes from ethanol ter, made basic with diluted sodium hydroxide solution My, 211 .212 C and extracted with benzene. The solvent is distilled off Analysis.Calcd. for C H O N-C H O N C, 61.01; under reduced pressure and 2.7 g. of crude product is 40 Found: obtained. An ethanolic solution of the product is re- Example 8 CH O cH o c n o C H O OCH3 [III] [VII fluxed with hydroxylamine hydrochloride (0.5 g.) and so- D-3,7-dimethoxy-4-phen0Xy-6 oxo N methylmordium acetate (0.5 g.) for one hour. The solvent is disphinan [III] (3.0 g.) is heated with concentrated hydrotilled off and the residue 1n water made alkaline with chloric acid (60 cc.) and amalgamated zinc (prepared from 20 g. of mossy zinc and 2 g. of mercuric chloride) D-3-n1ethoxy-4-phenoxy-6-oxo-7-hydroxy -N methylfor 6 hours and yields 2.36 g. of D-3-methoXy-4-phenoXy N methy1 A6 morphinan [VII]. The methanol A -morph1nan [V] (2.0 g.) 1s heated with concentrated duct, M.P. 91-96 C., is not depressed on admixture with hydrochloric acid (50 cc.) and ama g Zinc (P a sample obtained as in Example 7. 5 pared from 13 g. of mossy zinc and 1 g. of mercuric Example 9 chloride) for 6 hours and yields 1.62 g. of D-3-methoxy- [IV] [VII] D-3,7-dimethoxy 4 phenoxy 6,6 ethylenedioxy N- 4-phenoXy-N-methyl-A -morphinan [VII]. The methanol methylmorphinan [IV] is heated With e adduct, M.P. 91-96 C., is not depressed on admixture trated hydrochloric acid ('8 cc.) and amalgamated zinc ith a sample obt ined a in Example'l prepared from 6.5 g. of mossy zinc for 6 hours and yields 0.5 g. of D-3-methoxy-4-phenoXy-N-methyl-A -morphinan Example 11 [VI] [VII] [VII]. The methanol adduct, M.P. 91-96" C., is not D 3 methoXy-4- phenoxy-6,6;7,7-bisethylenedioXy-N- depressed on admixture with a sample obtained as in methylmorphinan [V1] is heated with amalgamated zinc Example 7. in concentrated hydrochloric acid in the similar manner Example 10 as described in the foregoing examples and yields D-3- methoxy-4-phenoxy-N-methyl-M-morphinan [VII]. The methanol adduct, 9196 C., is not depressed on admixture with a simple obtained as in Example 7.

Example 12 [VII] [X 16 of ether, the residue is crystallized from methanol and yields 4.45 g. of pure methanol adduct of D-3-methoxy-4- phenoxy-N-methyl-A -morphinan [VII], M.P. 98100 C.

[VII] (Purification of the compound [VII]) Crude methanol adduct of D-3-methoxy-4-phenoxy-N- Any impurity is not detected in thus purified product methyl-A -morphinan [VII] (10 g.) is dissolved in beneven by a gas-chromatographic analysis. [111 +88.6

zene (50 cc.) and then the benzene is distilled 01f. The same treatment is repeated to remove the methanol. To a solution of thus obtained free base in benzene (100 cc.) is added a benzene solution (58 cc.) of bromine (ben- (0.988% in ethanol).

The methiodide: M.P. 223-224 C. (recrystallized from acetone). +54.0 (0.764% in methanol).

A nalysiis.Calcd. for C24H2702N I zene:bromine=10:1) with stirring at 10 C. and allowed 30 C, 59.89; H, 6.46; N, 2.49; I, 22.60. Found: C, 60.03;

to stand over night. Precipitated crystals are collected by filtration and washed with benzene to give 4.085 g [VII] of hydrobromide of D-3-methoxy-4-phenoxy-6,7-dibromo- N-methylrnorphinan [XIII], M.P. 221222 C. (decomp.) (recrystallized from 99% ethanol).

The mother liquor is washed twice with 10% sodium hydroxide solution, concentrated to a half volume, shaken with 5% hydrochloric acid and allowed to stand to give 3.641 g. of crystals, M.P. 197-198 C. (hydrochloride of [XIII] Two layers of the mother liquor are separated. The benzene layer is shaken with 100 cc. of water and allowed to stand over night to yield 0.633 g. of crystals, M.P. 203-205 C. (hydrochloride of [XIH]).

Thus obtained salts of D-3methoxy-4-phenoxy-6,7-dibromo-N-methylmorphinan [XIII] are treated with 10% sodium carbonate solution to obtain the free base [XIII], M.P. 170171 C.

Analysis.-Calcd. for C H O NBr: C, 55.29; H, 5.22; N, 2.69; Br. 30.66. Found: C, 55.56; H, 5.24; N, 2.83; Br, 30.55.

A solution of the free base [XIII] (6.35 g.) in glacial acetic acid cc.) is heated with zinc dust (8.4 g.) for 3 hours on a boiling water bath with stirring. Upon cooling, the reaction mixture is made alkaline with aqueous ammonia and extracted with ether. After removal H, 6.49; N, 2.94; I, 22.78.

Example 13 A solution of crude D-3-methoxy-4-phenoxy-N-methyl-A -morphinan [VII] (17.50 g.) in chloroform cc.) is allowed to stand with benzoic acid (6.50 g.) and perbenzoic acid (14.71 g.) for 48 hours in a refrigerator. Then the reaction mixture is treated with 2.5% sodium carbonate solution and the chloroform is evaporated. The residue (23.12 g.) (N-oxide of D-3-methoxy-4-phenoxy-6,7-epoxy-N-methylmorphinan) is dissolved in methanol (250 cc.) and hydrogenated over Raney-Ni (19 g.). After absorption of 1180 cc. of hydrogen, the solution is filtered and evaporated. The residue (19.66 g.) is dissolved in benzene (500 cc.), treated with 2.5% sodium carbonate solution, and evaporated. The residue (16.87 g.) (D-3 methoxy 4-phenoxy-6,7-epoxy-N-methylmorphinan [XIV]) is dissolved in benzene (40 cc.) with benzoic acid (5.7 g.) by heating. After cooilng, precipitated crystals are collected by filtration and recrystallized from acetone to give benzoate of Formula XIV (10.96 g.), M.P. 174-175 C. The benzoate (1096 g.) is treated with 2% sodium carbonate solution and extracted with ether. After removal of the ether, the residue is crystallized from ether to give the free base of [XIV] (7.76 g.), M.P. 136138 C. [@1 3 +572 (0.030% in ethanol).

17 Analysis-Calm. for C H O N: C, 76.36; H, 7.21; N.3.71. Found: ,C, 76.67; H, 7.34; N, 3.80.

To a solution of D-3methoxy-4-phenoxy-6,7-epoxy- N-methylmorphinan [XIV] (7.76 g.) in chloroform (300 18 alumina to give 5.1 g. of pure D-3-methoxy-N-methyl-A morphinan, M.P. 8182 C. [a] l38.5 (1.103% in ethanol).

The picrate is prepared in and crystallizes from methcc.) is added another solution of hydrogen bromide (6.2 5 anol, M.P. 178a179 G.

g.) in chloroform (465 g.), keeping the temperature under C., and the mixture is allowed to stand at 0 C. for 40 minutes. After treatment with aqueous sodium bicarbonate solution, the chloroform is removed Analysis.-- Calcd. for C H ON-C H O N C, 57.82; H, 5.26; N, 11.24. Found: C, 57.91; H, 5.37; N, 11.04. The hydrobromide is crystallized from hot water, M.P. Ill-113 C. (decomp). [M +82.6 (1.062% in and the residue is crystallized from ether to give D-3- 10 water).

methoxy 4 phenoxy-6-bromo-7-hydroxy-N-methylmorphinan [XV] (8.68 g.), M.P. 117-118 c. +54.3 (0.879% in ethanol).

Analysis.-Calcd. for C H O NBr: C, 62.88; H, 6.16;

N, 3.06; Br, 17.43. Found: C, 62.58; H, 6.28; N, 3.10; 15 from ethanOLether, 230 C (d The hydrobromide: M.P. 187-188 C. (dec0mp.) The hydrochloride: M.P. 186'187 C. (decomp.)

[VII] depression of the melting point is observed on admixture with a pure sample obtained in Example 12.

Example 14 [VII] A solution of D-3methoxy-4-phenoxy-N-methyl-A morphinan [VII] (7.47 g.), purified by a method described in Example 12 or 13, in dry toluene (70 cc.) is added dropwise to liquid ammonia (300 cc.) (treated previously with a small amount of metallic sodium at to C.). Another 1.3 g. of metallic soduim is added to this stirred solution keeping the temperature at about 55 to 60 C. When a blue coloration has persisted for one hour, a small amount of ammonium chloride is added and the blue color disappears. Liquid ammonia is evaporated and the residue is treated with ether and the ether extracts are washed with diluted sodium hydroxide solution. The ether layer gives 5.4 g. of D-3- methoxy-N-methyl-A -morphinan, M.P. 81-82 C. The

Analysis.Calcd. for C H ON-HBr-H O: C, 58.69; H, 7.12; N, 3.80; Br, 21.70. Found: C, 58.39; H, 7.24; N, 4.05; Br, 21.26.

The methiodide is prepared in ethanol and crystallizes 113 +79.8 (0.747% in methanol).

Analysis.Calcd. for C H ON-CH I: C, 55.48; H, 6.37; N, 3.41. Found: C, 55.31; H, 6.54; N, 3.09.

Example 15 [VIII] A solution of D-3methoxy-4-phenoxy-N-methyl-A morphinan [VII] (0.98 g.), not purified, in dry ether (60 cc.) is added dropWise to liquid ammonia (150 cc.) (treated previously with a small amount of metallic so- 35 dium at 55 to 60" 0. Another 0.3 g. of metallic sodium is added to this stirred solution keeping the temperature at about 55 to 60 C. When a blue coloration persists for one hour, a small amount of ammonium chloride is added and color disappears. Working up in the similar manner to Example 14, D-3-methoxy-N-meth- [VIII] yl-A -morphinan [VIII] (0.68 g.) is obtained, M.P. 78- 85 C.

Analysis.Calcd. for C H ON: C, 80.25; H, 8.61; N, 5.20. Found: C, 80.03; H, 8.95; N, 4.98.

The melting point of this product is not depressed on admixture with a sample obtained as in Example 14.

The utilities hereinbefore enumerated for D-3-methoxy- A -rnorphinan are also applicable to the herein-disclosed quaternary and acid-addition salts thereof.

Suitable oral dosages for realizing such utilities range from about 5 milligrams to about 20 milligrams per day.

Having thus disclosed the invention, what is claimed is:

1. D-3methoxy-N-methyl-A -morphinan.

2. Quaternary salt of D-3methoxy-N-methyl-A -morproduct is dissolved in ether and chromatographed on phinan with lower alkyl halide.

19 3. Acid-addition salt of D-3-rnethoxy-N-methyl-A -morphinan with non-toxic acid selected from the group consisting of hydrogen halide, sulfuric acid and phosphoric acid.

References Cited by the Examiner UNITED STATES PATENTS 2,813,098 11/57 Tiffany 260-285 2,854,379 9/58 Fancher 16765 2,974,142 3/61 Grussner et a1. 260-285 3,035,977 5/62 Abood 16765 20 OTHER REFERENCES Gates et aL: J. Am. Chem. Soc., volume 80, page 1191 1958 Gates et 211.: J. Am. Chem. Soc., vol. 80, pages 1186-94 5 (1958).

Karrer: Organic Chemistry, 2d ed., pp. 92-102 (1946').

NICHOLAS S. RIZZO, Primary Examiner.

1 D. T. McCUTCHEN, Examiner. 

1. D-3-METHOXY-N-METHYL-$6-MORPHINAN. 